Sickle cell disease (SCD) is an inherited hemolytic anemia that affects more than 70,000 individuals in the US, primarily African-Americans, and millions more worldwide. The complications of SCD arise from vaso-occlusion resulting in interruption of blood flow to the tissues. Severe pain and damage in the affected tissue result in disability, repeated clinic visits and hospitalizations, along with significant health-care costs. A relatively inexpensive preventive therapy is especially important to this population, but there are few or no clinical trials to accomplish this. The currently available agents to prevent vaso-occlusion have several adverse effects associated with long-term therapy including adreno-cortical suppression, Cushing's syndrome, growth disturbances, osteoporosis, and immune suppression. and are not completely effective. Prior clinical experience and experimental observations suggest that anti-inflammatory therapy can effectively prevent vaso- occlusion, but there is a lack of potent and non-toxic agents that can be used on a long-term basis. A trial of anti-inflammatory therapy in SCD offers the great benefit of targeting a different pathophysiological mechanism than hydroxyurea, the current standard preventive therapy to reduce the frequency of vaso-occlusion in SCD. Hydroxyurea, an anti-neoplastic agent that interferes with cell division, induces fetal hemoglobin which antagonizes polymerization of the sickle hemoglobin in red blood cells. Because oxidant generation contributes to the development of inflammation in SCD, antioxidant therapy potentially offers a mechanism to reduce clinical symptoms. We administered 1-lipoic acid (LA) and acetyl-L-carnitine (ALCAR) - a potent antioxidant combination of two biochemicals with a known safety record - at our institution to 8 patients with SCD. The antioxidant therapy led to an improvement in the plasma glutathione redox status. The plasma concentration of serum C-reactive protein (CRP), a sensitive indicator of inflammation, was high at baseline in 4 subjects and returned to normal in 3 subjects after three weeks of antioxidant therapy. Plasma interleukin-6, another indicator of inflammation, also normalized after three weeks in the one subject with a high baseline level. Based upon these encouraging clinical results and our previous experimental observations, we hypothesize that LA/ALCAR will lower systemic inflammation in patients with SCD by reducing oxidative stress, which will result in a decrease in the frequency of vaso-occlusive pain episodes and improve their quality of life. We propose to conduct a randomized, double blind, placebo-controlled clinical trial of LA/ALCAR treatment for 6 months in 60 patients with SCD with five specific aims. We propose five specific aims to evaluate the impact of treatment on: (1) Average serum C-reactive protein value during the six months of treatment with LA/ALCAR;(2) Plasma concentrations of inflammatory cytokines, markers of endothelial activation, and monocyte activation;(3) Plasma and erythrocyte markers of oxidative stress;(4) Total number of vaso-occlusive episodes;and (5) Quality of life assessments. We expect that a decrease in inflammation in individuals with SCD would reduce the frequency of vaso-occlusive episodes. If this observation turns out to be true, it would provide valuable evidence for the role of inflammation in causing vaso-occlusion in humans with SCD.